Abstract
This article describes the design and synthesis of a series of novel amantadine-thiourea conjugates (3a–j) as Jack bean urease inhibitors. The synthesized hybrids were assayed for their in vitro urease inhibition. Accordingly, N-(adamantan-1-ylcarbamothioyl)octanamide (3j) possessing a 7-carbon alkyl chain showed excellent activity with IC50 value 0.0085 ± 0.0011 µM indicating that the long alkyl chain plays a vital role in enzyme inhibition. Whilst N-(adamantan-1-ylcarbamothioyl)-2-chlorobenzamide (3g) possessing a 2-chlorophenyl substitution was the next most efficient compound belonging to the aryl series with IC50 value of 0.0087 ± 0.001 µM. The kinetic mechanism analyzed by Lineweaver–Burk plots revealed the non-competitive mode of inhibition for compound 3j. Moreover, in silico molecular docking against target protein (PDBID 4H9M) indicated that most of the synthesized compounds exhibit good binding affinity with protein. The compound 3j forms two hydrogen bonds with amino acid residue VAL391 having a binding distance of 1.858 Å and 2.240 Å. The interaction of 3j with amino acid residue located outside the catalytic site showed its non-competitive mode of inhibition. Based upon these results, it is anticipated that compound 3j may serve as a lead structure for the design of more potent urease inhibitors.
Highlights
Urease or urea amidohydrolase is a metalloenzyme that holds two Ni+2 ions in its active site and is found in a variety of bacteria, fungi, algae, plants, certain invertebrates, soil, and ruminants
The signals at δ 136.16–127.7 ppm were assigned to aromatic carbons whilst the signals for sp3 hybridized carbons of the adamantyl group were assigned in their characteristic region
Compounds 3d with a 4-chloro substituent on the phenyl ring were found to be the most successful in the aryl series, while 3j with a 7-carbon alkyl chain was shown to be very effective in the alkyl series
Summary
Urease or urea amidohydrolase is a metalloenzyme that holds two Ni+2 ions in its active site and is found in a variety of bacteria, fungi, algae, plants, certain invertebrates, soil, and ruminants. As the amount of NH3 increases, the pH rises, allowing Helicobacter pylori, the bacteria that causes peptic ulcers, ulcerative colitis, and stomach cancer, to survive. Urease, is a nickel-dependent metalloenzyme found in plants, bacteria, and fungi. Bacterial enzyme is important because it has been shown to be a powerful virulence factor in various species. It is important for Helicobacter pylori metabolism and virulence, as both are required for penetration of the stomach mucosa, and it is a potent immunogen that evokes an effective immune response. It is no surprise that attempts to design, produce, and analyze novel urease inhibitors are a hot topic in biomedical sciences
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